Retinoid effects on inflammation and cell growth associated with endometriosis

描述（由申请人提供）：该项目的总体目标是了解类维生素a在子宫内膜异位症中的作用机制和临床潜力。我们认为类维生素a在子宫内膜异位症的发展中既起致病作用，又具有治疗潜力。为了支持这些假设，我们之前的工作已经证明类维生素a对子宫内膜异位症中某些异常的子宫内膜和免疫细胞功能有深远的影响，并被认为与其发病和/或进展有关。特别重要的是，我们提供的证据表明，类维甲酸可以改变子宫内膜细胞和巨噬细胞的活性，这对子宫内膜异位症患者有益。我们的总体目标将通过四个具体目标来实现。目的1将评估类维生素a水平是否在子宫内膜异位症中发生改变。这个问题将通过详细分析类维生素a在子宫内膜组织、腹膜免疫细胞和细胞所在的腹膜环境中的储存和代谢来解决。目的2将确定类视黄醇作用对子宫内膜异位症患者腹腔巨噬细胞CD36的生理影响。这种b型清除率受体在吸收和清除由于月经逆行而在腹膜上散布的凋亡细胞和细胞碎片中起主要作用。我们已经证明，这种受体在子宫内膜异位症女性的腹膜巨噬细胞中减少，维甲酸（RA）可以上调其表达。我们现在将确定CD36在子宫内膜异位症巨噬细胞中的异常调节的性质，以及RA是否可以用于使该受体的表达和功能正常化。通过我们的论证，类维生素a也可以改变参与子宫内膜间隙连接通信的某些连接蛋白（Cxs）的表达，Aim 3将验证我们的假设，即Cxs通过参与子宫内膜细胞生长、凋亡和侵袭潜能在子宫内膜异位症中发挥基础作用。这些研究将建立子宫内膜异位症病变中Cx异常表达与该病病因/进展之间的因果关系，并确定类视黄醛化合物调节子宫内膜细胞中Cx的能力。最后，Aim 4将在免疫功能小鼠模型中评估类维生素a对子宫内膜异位症发展的影响。使用模拟大规模逆行月经的方法，该模型还将阐明免疫调节与子宫内膜细胞异位生长之间的关系。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanism of action and clinical potential of retinoids in endometriosis. We propose that retinoids play both a causative role in the development of endometriosis and have therapeutic potential for its treatment. In support of these hypotheses, our previous work has demonstrated that retinoids have profound effects on certain endometrial and immune cell functions that are abnormal in endometriosis, and thought to be related to its pathogenesis and/or progression. Of particular importance, we provide evidence that retinoids can alter endometrial cell and macrophage activity in ways that would be expected to be beneficial to endometriosis subjects. Our overall goal will be accomplished by four specific aims. Aim 1 will assess whether retinoid levels are altered in endometriosis. This question will be addressed by detailed analyses of retinoid storage and metabolism in endometrial tissue, peritoneal immune cells, and the peritoneal milieu in which the cells reside. Aim 2 will determine the physiologic implications of retinoid action on CD36 as relates to peritoneal macrophages from women with endometriosis. This type-B scavenger receptor plays a primary role in the uptake and clearance of apoptotic cells and cell debris which seed the peritoneum as a result of retrograde menstruation. We have shown that this receptor is reduced in peritoneal macrophages from women with endometriosis and that retinoic acid (RA) can upregulate its expression. We will now determine the nature of the aberrant regulation of CD36 in endometriosis macrophages and whether RA can be used to normalize the expression and function of this receptor. Through our demonstration that retinoids can also alter the expression of certain connexins (Cxs) involved in endometrial gap junction communication, Aim 3 will test our hypothesis that Cxs play fundamental roles in endometriosis through their involvement in endometrial cell growth, apoptosis, and invasive potential. These studies will establish the cause and effect relationship between aberrant Cx expression in endometriotic lesions and the etiology/progression of this disease, and determine the ability to regulate Cxs in endometrial cells by retinoid compounds. Finally, Aim 4 will evaluate the effects of retinoids on the development of endometriosis in an immunocompetent mouse model. Using methodology that simulates a massive retrograde menses, this model will also shed light on the relationship between immune modulation and ectopic growth of endometrial cells. Project Narrative: Endometriosis is a major public health issue. Since current medical therapy has limitations, more effective treatment options are desperately needed. The information gained from our studies will provide the basic framework for the therapeutic use of retinoid compounds to impede the genesis and growth of endometriotic lesions.